Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKK?/NF-?B signaling. However, the role of IKK? in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKK? deficiency (driven by a SM22Cre-IKK?- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity, metabolic disorders, and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKK? positively regulates adipogenesis, indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKK? is essential for adipogenesis and atherogenesis, and that high-fat diet-induced IKK? activation promotes adipocyte differentiation and adipose inflammation, leading to increased obesity, insulin resistance, and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKK? in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKK? to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKK? by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKK? in adipogenesis and atherogenesis and will reveal a critical link between overnutrition, inflammation, and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKK? inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.